The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgement or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavor to which this specification relates.
Blending is the process of bringing distinct bulk material particles into close contact to produce a mixture of consistent quality as established by a pre-determined set of criteria. Blending of bulk solids is an important unit operation in many industries e.g., pharmaceuticals, cosmetics, food processing, metallurgy, mining, textiles, dyes, etc. The primary objective of the blending process is to manufacture a homogeneous product. For a homogeneous product it is imperative to inter-disperse particles of similar or diverse properties, uniformly. A mixture can be defined as homogeneous if every sample of the mixture has the same composition and properties as any other. The results can be presented as a standard deviation or relative standard deviation.
In a variety of pharmaceutical and non-pharmaceutical applications considerable effort in terms of resources and time is spent in developing a homogeneous blend. The phenomena of particle segregation and agglomeration present a challenge in developing a reproducible blending process. For dry particle mixing, the cohesive and adhesive forces acting between particles depend on molecular forces. Body forces (or gravitational forces) are proportional to the cube of the particle diameter, while Van der Waals forces are proportional to the particle diameter. Thus, for smaller particles (lesser than 10-20 μm), the inter-particle forces are significantly large compared to the particle weight. However most traditional powder technology applications do not deal with powders smaller than about 20 μm. This challenge is particularly exemplified in applications where the solid particulates to be blended are cohesive or partially cohesive in nature.
Particularly for the pharmaceutical applications and more particularly for pulmonary drug delivery, particles less than 5 μm are desired. This low particle size is required for efficient delivery of the active pharmaceutical ingredient (API) to the deep lungs. These micronized particles are typically manufactured using a dry or wet milling process and the high inter-particle forces due to small particle size make the solid API particulates very cohesive. The cohesive nature of the micronized API poses unique challenges in developing technologies for dry powder delivery of API to the lungs using delivery devices and technologies. At each stage during the dry powder inhaler (DPI) product life e.g., manufacture of the formulation, dose metering in primary package, storage, shipping and delivery to the patient, special methodologies have to be developed to minimize the impact of the cohesive nature of the API. In addition, dosage considerations require a diluent for potent molecules and/or additional excipients for formulation stabilization. As a result, several formulation approaches are utilized and a majority of these aim at improving the powder handling properties by creating blends with larger size particles.
The most common approach is to use particles that are larger or coarser (typically 40-100 μm) than that of the micronized API to act as carriers (e.g., lactose) of the micronized API when brought in contact with each other. The objective of the carrier particles is to improve micronized API flowability, thus improving dosing accuracy and minimizing the dose variability observed with cohesive micronized API alone. The success of this approach is limited by the cohesive and adhesive forces experienced by the particulates. The cohesive forces experienced by the micronized API and the carrier particles have to be overcome to adhere micronized API to the larger carrier particles. Moreover, the adherence of the micronized API has to be uniform throughout the distribution of the carrier particles to minimize blend variability and dose variability. For subsequent delivery of the API to the patient, the adhesive forces between micronized API and carrier particles have to be overcome. This phenomenon is typically facilitated by addition of a fraction of fine carrier particles (typically 1 to 20 μm) in the formulation to release the micronized API from the surface of the large carrier particles.
However, to practically manufacture blends of micronized and/or nano-sized API with micro and/or nano-particulate excipients is technically very challenging. This is due to the inherent cohesive nature of these components in their nascent state. In order to achieve a homogeneous blend the cohesive structures or agglomerates have to be destroyed. This challenge becomes particularly steep when more than one micronized API species has to be uniformly distributed in a blend. Moreover, the diverse and competing physical properties of multiple components make it a statistically improbable to achieve a multi-species homogeneous blend.
The prior art has described mechanical blenders that are available in a variety of operating principles, applications and scale. These include tumbling mixers, convective mixers, fluidized bed mixers, high-shear mixers, including media mills and hammer mills. Despite the plethora of blending hardware options available, manufacture of a homogeneous powder blend remains elusive because of the challenges described earlier.
The current best practice to commercially manufacture a dry powder blend of micronized API, microparticulate excipients and carriers for pulmonary drug delivery involves incorporation of these components in a staggered manner into a high shear blender. The high shear is applied in a continuous manner for prolonged period of time to de-agglomerate the micronized API until an acceptable content uniformity of micronized API in the blend is achieved. Blends of multiple APIs require several blending and processing steps making it technically complex and resource prohibitive.
Longer blending durations (typically ≥30 minutes for one API) are required to adequately de-agglomerate the micronized API and distribute uniformly in the powder bed with the various formulation components. Longer blending times are typically required to incorporate more than one API in the blend. Further, dispersion of particulates in the sub 1 μm range into particulates of 100-200 μm range can take well over 4 hours using conventional methods such as ball mills. However the higher energy input for a prolonged time period may also result in strong adherence of micronized API particles to the larger carrier particles surface. As mentioned earlier, this issue becomes particularly complex when more than one micronized API is present in the blend because of the differential cohesive and adhesive forces of the APIs with respect to the excipient components resulting in varying rates of mixing and transfer to the surface of the carrier particles.
The prolonged input of high shear energy may result in particle damage and mechanical and thermal induced physical and chemical degradation of the micronized API and excipients. Another common manifestation of physico-chemical changes due to prolonged high shear is exhibited by deposits of crystallized API(s) and/or excipients on the impeller blades, shaft or walls of the vessel. These deposits, which are primarily agglomerates of the API(s) do not get dislodged from the surfaces through the course of blending. This phenomenon result is significantly altered API content and degradation profile within the formulation. This in exhibited by batch to batch inconsistency and/or batch failure.
Another critical manifestation of altered physico-chemical properties due to prolonged input of high shear is tribo-electric charging. The tribo-electric charging of the dry powder blend is problematic for further handling of the powder during filling operation into the primary containers, emptying properties from the primary container and delivery performance because of the deposition on surfaces of the delivery devices. To dissipate the electrostatic charge built up as a result of the high shear forces applied, the high-shear blended powders are commonly stored at specifically controlled temperature and humidity conditions by controlled exposure to moisture. This process known as “conditioning” or “resting period” or “charge-dissipation” results in an additional cost burden due to time, storage and logistics required.
It is therefore desirable to develop improved processes for blending of micronized and/or nano-sized API, micro or nano-particulate excipients and carrier components, which may address one or more of the disadvantages discussed above. It is further advantageous to produce a uniform powder blend, particularly for particles sized for pulmonary administration, which can be produced in a single step. What is required is a process that overcomes one or more of the problems of the prior art. Such a simplified process reduces the risk of batch to batch inconsistency, batch failure and product loss, minimizes the handling and conditioning stages, thereby reducing the time and cost of the current multi-step blending processes.